A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.
Int J Mol Sci
; 19(8)2018 Aug 01.
Article
in En
| MEDLINE
| ID: mdl-30071673
ABSTRACT
Lymphedema is characterized by chronic swelling of any body part caused by malfunctioning or obstruction in the lymphatic system. Primary lymphedema is often considered genetic in origin. VEGFC, which is a gene encoding the ligand for the vascular endothelial growth factor receptor 3 (VEGFR3/FLT4) and important for lymph vessel development during lymphangiogenesis, has been associated with a specific subtype of primary lymphedema. Through Sanger sequencing of a proband with bilateral congenital pedal edema resembling Milroy disease, we identified a novel mutation (NM_005429.2; c.361+5G>A) in VEGFC. The mutation induced skipping of exon 2 of VEGFC resulting in a frameshift and the introduction of a premature stop codon (p.Ala50ValfsTer18). The mutation leads to a loss of the entire VEGF-homology domain and the C-terminus. Expression of this Vegfc variant in the zebrafish floorplate showed that the splice-site variant significantly reduces the biological activity of the protein. Our findings confirm that the splice-site variant, c.361+5G>A, causes the primary lymphedema phenotype in the proband. We examine the mutations and clinical phenotypes of the previously reported cases to review the current knowledge in this area.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Arthrogryposis
/
Hand Deformities, Congenital
/
Clubfoot
/
RNA Splicing
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Frameshift Mutation
/
Cleft Palate
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Vascular Endothelial Growth Factor C
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Animals
/
Child, preschool
/
Female
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Humans
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Infant
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Male
/
Newborn
Language:
En
Journal:
Int J Mol Sci
Year:
2018
Type:
Article
Affiliation country:
United kingdom